Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk

Abstract

Compositions and methods comprising at least one biguanide compound and at least one statin combined with at least one additional active agent in fixed dose combinations are provided for reducing cardiometabolic risk, and for the treatment of cardiovascular disease, wherein the biguanide compound is formulated for delayed release.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to reducing cardiometabolic risk in a comprehensive and concerted fashion in patients in need thereof, by administering a fixed dose combination therapy comprising at least one biguanide, at least one statin and at least one additional active agent in a unitary dosage form.BACKGROUND OF THE INVENTION[0002]Cardiovascular disease (CVD) generally includes coronary artery disease, cerebrovascular disease and peripheral arterial disease, and is the major cause of morbidity and mortality in the Western world. (Brunzell et al. Lipoprotein Management in Patients with Cardiometabolic Risk, Diabetes Care 2008 31: 811-822). Notwithstanding significant improvements in therapeutic options over the last few decades, the initial presentation of coronary arterial disease in particular manifests as sudden death in up to one-third of patients. Id. Accordingly, better and more effective intervention options are still needed to prevent...

AI Technical Summary

Benefits of technology

[0008]The present invention provides more comprehensive and effective combination therapies for reducing cardiometabolic risk in patients in need thereof, and for treating and / or preventing cardiovascular disease, employing at least one biguanide, at least one statin and at least one additional active agent. As demonstrated herein, biguanides such as metformin can be administered with significantly reduced gastrointestinal complications using delayed release (DR) formulations, thereby enabling safe and effective administration of combinations of biguanides, statins and other active agents to a much broader patient population in unitary pharmaceutical compositions. Moreover, and remarkably, even once-a-day dosing of biguanides can be done with full therapeutic efficacy at the reduced dosages described and claimed herein.

[0024]Advantageously, the metformin or other biguanide is formulated for delayed release so as to minimize the systemic bioavailability of the biguanide compound in the patient. In particular embodiments, administration of the subject delayed-release formulation minimizes the mean plasma AUC, the mean plasma Cmax and / or the circulating plasma concentration of the biguanide compound in the patient compared to an identical protocol administering an IR or XR formulation having the same amount of the biguanide compound. In preferred embodiments, the biguanide compound is metformin, the IR composition is Glucophage® and the XR composition is Glucophage® XR.

Problems solved by technology

Notwithstanding significant improvements in therapeutic options over the last few decades, the initial presentation of coronary arterial disease in particular manifests as sudden death in up to one-third of patients.

When patients have one or more of these risk factors and are physically inactive or smoke, their cardiometabolic risk increases even further.

Even with adequate cholesterol lowering, however, many patients on statin therapy still have significant CVD risk.

Notably, however, to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications.

1996 Feb. 29; 334(9) Unfortunately, however, metformin also produces significant gastrointestinal complications that have restricted its use beyond diabetic patients per se, and it is further contraindicated in patients having hypoxic conditions caused by, e.g. respiratory or heart failure.

Moreover, conventional dosing strategies require a gradual dose escalation from 500 mg bid up to 1000 mg bid for a daily maximum dose of 2000 mg, with further uptitration to as much as 3000 mg / day to achieve appropriate glycemic control, severely limiting the ability of formulators to combine it with additional active agents in fixed dose combination therapies.

To date, it has proven difficult to effectively combine metformin with multiple active agents in the same single-dose formulation.

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